The sympathetic nervous system (SNS) plays a pivotal role in both cardiovascular and metabolic regulation. Prospective cohort, offspring and clinical studies indicate that elevated SNS activity is an early pathophysiological phenomenon that predicts future metabolic abnormalities (insulin resistance, hyperglycemia, type 2 diabetes, dyslipidemia and adiposity), increases in blood pressure and cardiovascular risk. In established obesity several factors act in concert to maintain chronic elevation of central sympathetic drive to skeletal muscle, the kidneys and the heart. Primary amongst these are hyperinsulinemia, impaired baroreflex function, sleep apnoea and elevated adipokine levels.
Using the techniques of clinical microneurography to quantify sympathetic nerve firing rate in skeletal muscle vasculature and isotope dilution to estimate total body noradrenaline spillover rate, our group has demonstrated associations between SNS activity and insulin resistance and insulin clearance (inverse) in obese cohorts. Furthermore, insulin resistant obese individuals display blunted postprandial sympathetic response to oral carbohydrate loading compared with age- and body mass index-matched insulin sensitive controls. This is relevant to body weight homeostasis, given that facultative thermogenesis accounts for 3-4% of daily energy expenditure. The sympathetic neural signal is also modified by the rate of removal of noradrenaline from the neuroeffector junction and plasma compartment. We recently reported reduced plasma noradrenaline clearance in obese treatment naïve type 2 diabetic patients compared with controls with impaired glucose tolerance. This was attributed to reduced peripheral noradrenaline transporter (NET) expression, and haemoglobin A1C was an independent inverse predictor of NET levels.
Weight loss and exercise are first line treatments for the metabolic syndrome that elicit sympathoinhibitory effects and reverse blunted postprandial sympathetic response in insulin resistant states. The magnitude of sympathoinhibition is greatest in hyperinsulinemic subjects. Insulin-sensitizing, oral hypoglycemic and sympathomoderating drugs may offer other approaches to modify sympathetic drive and protect against target organ damage and metabolic derangement.